Substituted cyclohexene derivatives as HMG-CoA reductase inhibitors

ABSTRACT

Disclosed are novel 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors useful as antihypercholesterolemic agents represented by the formula ##STR1## and the corresponding ring-opened hydroxy acids derived therefrom and pharmaceutically acceptable salts thereof. 
     Pharmaceutical compositions containing said compounds and method of inhibiting the biosynthesis of cholesterol therewith are also disclosed.

BACKGROUND OF THE INVENTION

This application is a continuation-in-part application of United StatesPatent Application Ser. No. 07/510,351 filed Apr. 17, 1990, now U.S.Pat. No. 5,001,144 issued Mar. 19, 1991 which, in turn is acontinuation-in-part of United States Application Ser. No. 07/412,356filed Sept. 25, 1989 now U.S. Pat. No. 4,939,143 issued Aug. 3, 1990,which, in turn, is a continuation-in-part application of United StatesApplication Ser. No. 07/328,836 filed Mar. 27, 1989 U.S. Pat. No.4,900,754 issued Feb. 13, 1990.

1. Field of the Invention

The present invention relates to compounds, pharmaceutical compositionsand a method useful for reducing serum cholesterol in humans. Moreparticularly, the invention relates to substituted cyclohexenederivatives, the corresponding ring opened hydroxy acids derivedtherefrom and pharmaceutically acceptable salts thereof which are potentinhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme Areductase (hereinafter HMG-CoA reductase), pharmaceutical compositionsthereof, and a method of inhibiting biosynthesis of cholesterol for thetreatment of atherosclerosis, hyperlipidemia and hypercholesterolemia.

2. Related Prior Art

Inhibitors of HMG-CoA are effective in lowering blood plasma cholesterollevel as well as inhibiting the biosynthesis of cholesterol in humans.As such, inhibitors of HMG-CoA are useful in the prevention andtreatment of coronary heart diseases. The prior art recognizes theimportance of such compounds, e.g., Bethridge et al., Brit. Med. J.,4,500 (1975) and Brown et al., Scientific American, 58 Nov. (1984).Illustrative references directed to such compounds follow.

U.S. Pat. No. 4,681,893 to B. D. Roth pertains to trans-6-[2-(3-or4-carboxamido-substituted pyrrol-1-yl)alkyl]- 4-hydroxypyran-2-onesuseful as hypocholesterolemic agents.

U.S. Pat. No. 4,668,699 to Hoffman et al. discloses semi-syntheticanalogs of compactin and mevinolin and the dihydro and tetrahydroanalogs thereof for antihypercholesterolemic application.

U.S. Pat. No. 4,567,289 relates to ,methyl, ethyl, n-propyl,2-(acetylamino)ethyl, or 1-(2,3-dihydroxy)propyl ester ofE-(3R,5S)-7-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoicacid that are HMG-CoA reductase inhibitors.

U.S. Pat. No. 4,611,067 discloses a process for the preparation ofHMG-CoA reductase inhibitors which contain a4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.

European Patent Application No. 87,305,527.1 (Publication No. 0,251,625)discloses HMG-CoA.reductase inhibitors having the structures I and II.##STR2##

SUMMARY OF THE INVENTION

In accordance with the present invention, certain substitutedcyclohexene derivatives, the corresponding ring opened hydroxy acidsderived therefrom and pharmaceutically acceptable salts thereof areprovided which are potent inhibitors of HMG-CoA reductase. Specifically,the invention provides compounds of formula I. ##STR3## wherein: (a) Inone embodiment of the invention:

A is CH₂ --CH₂, CH═CH or --C═C--;

X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl, halogen, RO(CH₂)_(m) --,aryl, NR₁ R₂ or SO_(m) R₁ ;

Y is azetidyl, pyrrolidyl, pyrrolyl, piperidyl, pyridyl, succinimido orphthalimido;

R, R₁, R₂ and Z are independently: H or C₁₋₆ alkyl;

m is 0, 1 or 2; its hydroxy acids and the pharmaceutically acceptablesalts thereof.

Examples of this embodiment are the following compounds:

1.trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-1hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

2.trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-succinimido-6,6-dimethylcylcohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

3.trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-phthalimido-6,6-dimethylcylcohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

4.trans-6-{2-(2-(4-fluorophenyl)-4-(pyridin-4-yl)-6,6-dimethylcylcohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;and

5.trans-6-{2-{2-(4-fluoro-3-hydroxymethyl)-4-(piperdin-1-yl)-6,6-dimethylcylcohex-1-en-1-yl}ethyl-}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(b) In the second embodiment of the invention of formula I:

7 A is CH₂ CH₂, CH═CH or C═C;

X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl, halogen, RO(CH₂)_(m) --,aryl, NR₁ R₂ or SO_(m) R₁ ;

Z is a chemical bond;

Y is --O(CR₁ R₂)_(n) O-- or --S(CR₁ R₂)_(n) S-- and Z and Y are joinedtogether and form a heterocyclic ring with the carbon atom of thecyclohexene ring;

R, R₁ and R₂ are independently: H or C₁₋₆ alkyl;

n is 2, 3 or 4;

m is 0, 1 or 2; its hydroxy acids and pharmaceutically acceptable saltsthereof.

Examples of this embodiment are the following compounds:

1.trans-(E)-6-(2-{7-(4-fluorophenyl)-9,9-dimethyl-1,4-dioxaspiro[4.5]dec-7-en-8-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

2.trans-(E)-6-{2-(8-(4-fluorophenyl)-10,10-dimethyl-1,5dithiaspiro{5.5}undec-8-en-9-yl}ethenyl}-4-hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one;

3.trans-6-{2-{8-(4-fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiaspiro(5.5}undec-8-en-9-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

4.trans-(E)-6-{2-{8-(4-fluoro-3-hydroxymethyl)-10,10-dimethyl-1,5-dithiaspiro{5.5}undec-8-en-9-yl}ethenyl}-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;and

5.trans-6-{2-{8-(4-chloro-3-fluorophenyl)-10,10-dimethyl-1,5-dithiaspiro{5.5}undec-8-en-9-yl}ethyl-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

(c) In the third embodiment of the invention of formula I:

A is CH₂ CH₂, CH═CH, or C═C;

X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl, halogen, RO(CH₂)_(m) --;aryl, NR₁ R₂ or SO_(m) R₁ ;

R, R₁, R₂ and Z are independently: H or C₁₋₆ alkyl;

Y is ##STR4## Q is NR₃ R₄ or OR₃ ; R₃ and R₄ are independently: H, C₁₋₆alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

m is 0,1 or 2; its hydroxy acids and pharmaceutically acceptable saltsthereof.

Examples of this embodiement are the following compounds:

1.trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-phenylcarbamoyloxy-6,6-dimethylcyclohex-1-en-1-yl}ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

2.trans-(E)-6-{2-{2-(4-fluoro-3-hydroxymethyl)-4-(4-fluorophenylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2one;

3.trans-6-{2-{2-(4-fluorophenyl)-4-(N-phenyl-N-methylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

4.trans-(E)-6-{2-{2-(4-chlorophenyl)-4-(3-pyridylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

5.trans-(E)-6-{2-{2-(4-fluorophenyl)-4-ethylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;and

6.trans-(E)-6-{2-{2-(4-chloro-3-methylphenyl)-4-(4-chloro-3-methylphenylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5',6-tetrahydro-2H-pyran-2-one.

(d) In the fourth embodiment of the invention of formula I:

A is CHzCH₂, CH═CH, or C═C;

X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl, halogen, RO(CH₂)_(m) --,aryl, NR₁ R₂ or SO_(m) R₁ ;

R, R₁, R₂ and Z are independently: H or C₁₋₆ alkyl;

Y is --O(CR₁ R₂)_(n) C(O)Q;

Q is NR₃ R₄ or OR₃ ;

R₃ and R₄ are independently: H, C₁₋₆ alkyl, aryl, substituted aryl orheteroaryl;

n is 1,;2 or 3;

m is 0, 1 or 2; its hydroxy acids and pharmaceutically acceptable saltsthereof.

Examples of this embodiment are the following compounds:

1.trans-6-(2-{2-(4-fluoro-3-methylphenyl)-4-ethoxycarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

2.trans-(E)-6-{2-{2-(4-fluorophenyl)-4-(2-(ethoxy-carbonyl)ethoxy)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2one;

3.trans-(E)-6-{2-{2-(4-fluoro-3-ethylphenyl)-4-(2-(4-fluoroanilinocarbonyl)ethoxy)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

4.trans-(E)-6-{{2-(4-chlorophenyl)-4-(dimethylaminocarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl}ethynyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;and

5.trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-(4-methoxyanilinocarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

DETAILED DESCRIPTION OF THE INVENTION

Unless expressly indicated otherwise herein, alkyl representsstraight-chain or branched chain alkyl; aryl preferably denotes phenylor naphthyl; substituted aryl means aryl substitution with hydrogen,C₁₋₆ alkyl, halogen, RO(CH₂)_(m), NR₁ R₂ or SO_(m) R₁ wherein R, R₁, R₂and m are as previously defined; preferred heteroaryl are pyridyl,indolyl and quinolyl; substituted heteroaryl means heteroarylsubstituted with hydrogen, C₁₋₆ alkyl, halogen, RO(CH₂)_(m), NR₁ R₂ orSO_(m) R₁ wherein R, R₁, R₂ and m are as previously defined; halogendenotes Cl, F, Br and I; and alkoxy means C₁₋₆ alkoxy.

The pharmaceutically acceptable salts of the present invention includethose formed from sodium, potassium, calcium, aluminum, lithium,magnesium, zinc, lysine, arginine, procaine, ethylenediamine andpiperazine.

The invention encompasses optical and stereoisomers of the compounds andmixtures thereof defined by the structural formulas.

The procedures for producing the compounds of the present invention areas indicated in Schemes I through IX which follow. ##STR5## ##STR6####STR7## ##STR8##

The starting materials were obtained from the Aldrich Chemical Co. butthey may also be synthesized in accordance with methods known in theart.

The following preparative examples will further illustrate theinvention. In the examples, the underlined parenthetical numbers from 1through 45 refer to and identify the structures shown in Schemes Ithrough IX.

EXAMPLE 1 (Scheme I) A. Methyl3.3-dimethyl-2-(4-fluoro-3-methylbenzovl)-5-oxohexanoate (3a)

A mixture of methyl 4-fluoro-3-methylbenzoylacetate (1a) (26.95g, 0.128mol) and mesityl oxide (2) (19.3g, 0.192 mol) was kept at 0°-5° C. for 5days, poured onto cold saturated NaHCO₃ and extracted with ether. Thecombined extracts were washed with H₂ O and brine and dried (MgSO₄).Removal of the volatiles in vacuo furnished 3a which was used withoutfurther purification.

B. Methyl2.2-dimethyl-6-(4-fluoro-3-methylohenyl)-cyclohex-5-en-1-carboxylate(4a)

A solution of 3a and Triton B (25 mL of 40% in methanol) in 200 mLanhydrous methanol was heated at reflux for 1 hour, cooled, acidifiedwith aqueous HCl and extracted with ether. The combined extracts werewashed with H₂ O and brine and dried (MgSO₄). Removal of volatiles invacuo and purification of the residue by HPLC using 8:1 hexanes: EtOAcas eluents provided 22.5 gm of the solid product.

C. Methyl8-(4-fluoro-3-methylohenyl)-10,10-dimethyl-1.5-dithiaspiro{5.5)undec-7-en-9-carboxvlate(5)

To a solution of 4a (7.75 g, 26.7 mmol) and 1,3-propanedithiol (3.03g,28.1 mmol) in 50 mL acetic acid was added boron trifluoride etherate(7.98g, 56.2 mmol). The solution was stirred overnight, diluted withether, washed with H₂ O, saturated NaHCO₃, and brine and dried (MgSO₄).Removal of the volatile in vacuo provided a residue which wascrystallized from hexane, wt 8.0 g, mp 100°-01° C. Anal. C₂₀ H₂₅ FO₂ S₂: Theory C: 63.12; H:6.62; S:16.85. Found C: 63.45; H:6.58; S: 16.44.

D.8-(4-Fluoro-3-methylphenyl)-9-hvdroxvmethyl-10,10-dimethyl-1,5-dithiasoiro5.5)undec-7-ene(6)

To a solution of 5 (7.77 g, 20.4 mmol) in 80 mL of anhydrous THF at0°-5° C was added portionwise LAH (0.97 g, 25.6 mmol). The mixture wasstirred for 1.5 h, quenched with 1 mL of H₂ O, 1 mL of 15% NaOH and 3 mLof H₂ O and filtered. The volatiles were removed in vacuo and theresidue recrystallized with hexanes:EtOAc. Wt. 5.55 g. mp 128°-9° C.Anal. C₁₉ H₂₅ FOS₂ ; Theory C: 64.74; H: 7.15; S:18.19. Found C: 64.57;H: 7.03; S: 17.71.

E.8-(4-Fluoro-3-methylphenyl-10,10-dimethyl-1,5-dithiaspiro(5.5)undec-7-en-9-carboxaldehvde(7)

To a solution of 6 (5.6 g, 16.6 mmol) and triethylamine (15 mL, 107mmol) in 50 mL anhydrous DMSO was added sulfur trioxide pyridine complex(8.1 g, 49.7 mmol). The mixture was stirred for 1 h, at ambienttemperature and under a N₂ atmosphere, diluted with ether, washedthoroughly with H₂ O and brine and dried (MgSO₄). Removal of thevolatiles in vacuo provided a residue which was purified by HPLC using17:1 hexanes:EtOAc as eluents. Concentration in vacuo of theproduct-rich fractions furnished 3.90 gm of product.

F.8-(4-Fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiaspiro(5.5)undec-8-en-9-carboxaldehvde(8)

To a solution of (3.90 g, 11.1 mmol) in 30 mL anhydrous methanol at0°-5° C was added dropwise Triton B (0.23 g, 0.55 mmol, 40% inmethanol). The mixture was kept at 0°-5° C overnight, diluted withacetic acid (2 mL), ether and H₂ O . The organic layer was washed withH₂ O and brine and dried (MgSO₄). Removal of the volatiles in vacuoprovided a residue which was purified by HPLC using 40:1 hexanes:EtOAcas the eluents. Concentration in vacuo of the product-rich fractionsgave 3.50 gm of the solid product.

G.(E)-3-{8-(4-fluoro-3-methylohenyl)-10,10-dimethyl-1,5-dithiaspiro(5.5)undec-8-en-9-vl)orooenal(9)

To a -20° C. solution of LDA (19.0 mmol) in 60 mL anhydrous THF wasadded ethylidenecyclohexylamine (Org. Syn. 50, 66) (2.38 gm, 19.0 mmol).The solution was stirred for 30 min, cooled to -78° C. and a solution of8 (3.50 g, 10.0 mmol) in 60 mL was added. The mixture was stirred for 3h, diluted with ether and quenched with H₂ O . The organic layer waswashed with H₂ O and brine and dried (MgSO₄). Removal of the volatilesin vacuo and purification of the residue by HPLC using 10:1hexanes:EtOAc provided 1.6 g of the orange color gum.

H. Methyl(E)-7-{8-(4-fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiasoiro{5,5)undec-8-en-9-yl)-5-hvdroxv-3-oxohept-6-enoate(10)

To a -60° C. solution of LDA (15.0 mmol) in 15 mL anhydrous THF wasadded dropwise methyl acetoncetate (0.592 g, 5.1 mmol). The solution waswarmed to 0° C. , stirred for 1 h and a solution of 9 (1.6 g, 4.25 mmol)in 15 mL anhydrous THF was added. The mixture was stirred for 1 h, andquenched with acetic acid (1 mL), H₂ O and ether. The organic layer waswashed with H₂ O, saturated NaHCO₃ and brine and dried (MgSO₄) Removalof the volatiles in vacuo and purification of the residue by HPLC using3:1 hexanes:EtOAc as elevents furnished 1.4 g of rust colored oil.

I. Methyl(E)-7-(8-(4-Fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiaspiro(5.5)undec-8-en-9-yl)-3,5-dihydroxy-hept-6-enoate(11)

To a solution of 10 (1.4 g, 2.84 mmol) and triethyl borane (4.3 mL, 4.26mmol) in 12 mL anhydrous THF which was stirred at ambient temperaturefor 5 min., cooled to -78° C. and NaBH₄ (0.125 g, 3.27 mmol) was addedfollowed by the slow dropwise addition of anhydrous methanol (2mL). Themixture was stirred for 45 min., quenched with aqueous H₂ O₂ (1.9 mL ofa 6:13 mixture Of 30% H₂ O₂ -H₂ O mixture), warmed to ambienttemperature over 1 h and diluted with EtOAc and aqueous HCl. The organiclayer was washed with H₂ O, and brine and dried (MgSO₄) Removal of thevolatiles and purification of the residue by HPLC using 2:1hexanes:EtOAc as eluents yielded 1.1 g of tan colored gum.

J.(E)-3,5-dihydroxy-7-{8-(4-fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiaspiro(5,5}undec-8-en-9-yl}hept-6-enoicacid (12)

To a solution of 11 (1.05 g, 2.12 mmol) in 10 mL of methanol at 0°-5° C.was added dropwise aqueous NaOH (2.1 mL of 1N, 2.1 mmol). The mixturewas stirred for 1 h and most of the volatiles were removed in vacuo. Theresidue was acidified with aqueous HCl to pH 3 and extracted with ether.The combined extracts were washed with brine and dried (MgSO₄). Removalof the volatiles in vacuo gave 0.90 gm of tan colored solid.

K. Trans-(E)-6-(2-(8-(4-fluoro-3-methylphenyl)-10,10-dimethyl-1,5-dithiaspiro(5,5)undec-8-en-9-yl)ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(13)

To a 0°-5° C. solution of 12 (0.90 gm, 1.87 mmol) and triethylamine (315μL, 2.25 mmol) in 10 mL CH₂ Cl₂ was added dropwise ethyl chloroformate(185 μL, 1.87 mmol). The mixture was stirred for 30 min, diluted withether, washed with H₂ O , saturated NaHCO₃ and brine and dried (MgSO₄).Removal of the volatiles in vacuo and purification of the residue bySiO₂ using 3:2 hexanes:EtOAc as eluent provided 0.61 g of the product.mp 136°-8° C. Anal. C₂₃ H₃₁ FO₃ S₂ : Theory C: 64.91; H: 6.75. Found C:65.31; H: 6.82.

EXAMPLE 2 (Scheme II) A. Methyl2-(4-fluoro-3-methylphenyl)-4-hydroxy-6,6-dimethyl-cyclohex-2-en-1-carboxylate(14)

To a solution of 4a (13.7 g, 47.2 mmol) in 100 mL of methanol at 0°-5°C. was added NaBH₄ (2.68 g, 70.9 mmol). The mixture was stirred for 1hr, diluted with ether and H₂ O. The organic layer was washed with H₂ Oand brine and dried (MgSO₄). Removal of the volatiles in vacuo provideda quantitive yield of product which was taken forward without furtherpurification.

B. Methyl2-(4-fluoro-3-methylphenyl)-4-t-butyldimethylsilyloxy)-6.6-dimethylcyclohex-2-en-l-carboxylate(15)

To a solution of imidazole (9.75 g, 0.142 mmol) in 100 H mL CH₂ Cl₂ wasadded dropwise a solution of t-butylchlorodimethylsilane (11.0 g, 70.8mmol) in 50 mL CH₂ Cl₂. The mixture was stirred for 15 min., a solutionof 14 (47.2 mmol) in 100 mL of CH₂ Cl₂ was added, stirred for overnightand diluted with ether and H₂ O . The organic layer was washed with H₂ Oand brine and dried (MgSO₄). Removal of the volatiles in vacuo provideda quantitative yield of 15 which was taken forward without furtherpurification.

C.1-(4-Fluoro-3-methylphenyl)-3-[t-butyldimethylsilyloxy)-5,5-dimethyl-6-hydroxymethylcyclohexene(16)

In a manner similiar to Scheme I, 15 (47.2 mmol) was treated with LAH(94.4 mmol) in THF and, after workup, and purification by HPLC using 8:1hexanes:EtOAc as eluent provided 6.55 g of oily product.

D.2-(4-Fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6,6-dimethylcyclohex-2-en-1-carboxaldehyde(17)

In a manner similiar to Scheme I, 16 (43.5 g, 0.115 mol) was treatedwith sulfur trioxide pyridine complex (56.0 g, 0.345 mol) in anhydrousDMSO and workup provided 21.6 g of brown oil which was taken forwardwithout additional purification.

E.2-(4-Fluoro-3-methylphenyl)-4-t-butyldimethylsilyloxy)-6,6-dimethylcyclohex-l-en-1-carboxaldehyde(18)

A solution of 17 (21.6 g, 57.4 mmol) and potassium t-butoxide (0.32 g,2.87 mmol) in 250 mL anhydrous THF was stirred for 2 h and poured ontoether and dilute aqueous acetic acid. The organic layer was washed withH₂ O, saturated NaHCO₃ and brine and dried (MgSO₄). Removal of thevolatiles in vacuo provided 20.2 g of yellow oil which was taken forwardwithout further purification.

F.(E)-3{(2-(4-fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6,6-dimethylcyclohexen-1-yl)propenal(19)

In a manner similiar to Scheme I, 18 (20.2 g, 53.6 mmol) was treatedwith LDA-derived anion of ethylidenecyclohexylamine (12.8 g, 0.102 mol)and, after workup and purification by HPLC using 30:1 hexanes:EtOAc aseluent provided 13.5 g of an orange color oil.

G. Methyl(E)-7-(2-(4-fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6,6-dimethylcyclohexen-1-yl}-5-hydroxy-3-oxohept-6-enoate

In a manner similiar to Scheme I, 19 (13.45 g, 33.4 mmol) was treatedwith LDA-derived dianion of methyl acetoacetate (40.1 mmol) in THF and,after workup and purification by HPLC using 4:1 hexanes:EtOAc as eluentprovided 7.8 g of an orange color oil.

H. Methyl(E)-7-(2-(4-fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6.6-dimethylcyclohexen-1-yl}-3,5-dihydroxyhept-6-enoate

In a manner similiar to Scheme I, 20 (7.80 g, 15.1 mmol) was treatedwith triethylborane (22.6 mmol), NaBH₄ (17.3 mmol) and methanol (10 mL)in anhydrous THF at -78° C. . The workup provided 7.55 g of product asan oil which was taken forward without further purification.

I.Trans-(E)-6-(2-{2-(4-fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6,6-dimethylcyclohexen-1-yl)-ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(22)

In a manner similiar to Scheme I, 21 (7.55 g, 14.5 mmol) was treatedwith aqueous NaOH (14.5 mmol) in methanol at 0°-5° C. and after theusual workup provided 6.9 gm of acid. The acid (13.6 mmol) was treatedwith ethyl chloroformate (13.6 mmol) and triethylamine (13.6 mmol) inCH₂ Cl₂. Purification by HPLC using 2:1 hexanes:EtOAc as eluentfurnished 4.8 g of solid product.

J. Trans(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-(t-butyldimethylsilyloxy)-6,6-dimethylcyclohexen-1-yl)-ethenyl)-4-t-butyldiphenylsilyloxy)-3.4,5.6-tetrahydro-2H-pyran-2-one(23)

To a solution of imidazole (1.84 g, 27.0 mmol) andtbutylchlorodiphenylsilane (3.71 g, 13.5 mmol) in 40 mL CH₂ Cl₂ wasadded a solution of 22 (4.40 g, 9.0 mmol) in 40 mL of CH₂ Cl₂. Thereaction mixture was stirred overnight, diluted with ether, washed in H₂O and brine and dried (MgSO₄). Removal of the volatiles in vacuoprovided a quantitative yield of the oily product.

K.Trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-hydroxy-6,6-dimethylcyclohexen-1-yl)ethenyl)-4-t-butyldiphenylsilyloxy)-3,4,5,6-tetrahydro-2H-ovran-2-one(24)

A solution of 23 (6.5 g) in 90 mL acetic acid, 30 mL THF and 30 mL H₂ Owas stirred overnight at ambient temperature and most of the volatileswere removed in vacuo. The residue was diluted with ether, washed withH₂ O and brine and dried (MgSO₄). Removal of the volatiles in vacuofurnished a residue which was purified by HPLC using 2:1 hexanes:EtOAcas eluent. Concentration in vacuo of the product-rich fractionsfurnished 4.6 g of product.

EXAMPLE 3 (Scheme III) A. Methyl7-(4-fluorophenyl)-9.9-dimethyl-1,4-dioxaspiro-(4,5)-dec-6-en-8-carboxylate(25)

A solution of 4b (11,51 g, 41.7 mmol) 1,2-ethanediol (5.81 mL, 104 mmol)and PPTS (2.09 g, 8.34 mmol) in 100 mL toluene was heated withazeotropic removal of H₂ O for 6 h, 1,2-ethanediol (2.9 mL) was addedand heated overnight. The solution was cooled, diluted with ether,washed with saturated NaHCO₃, H₂ O and brine and dried (MgSO₄). Removalof the volatiles in vacuo provided the oily product.

B.7-(4-fluorophenyl)-9,9-dimethyl-1,4-dioxaspiro{4,5}-dec-7-en-8-carboxaldehyde(26)

To a solution of 25 (11.2 g, 35.0 mmol) in 100 mL of anhydrous THF at0°-5° C. was added portionwise LAH (52.5 mmol). The mixture was stirredfor 2 h and work-up provided 9.71 g of the oily alcohol. A mixture ofthe alcohol (97.1 g, 33.2 mmol), PCC (33.2 mmol) and celite (4 g) in 90mL CH₂ Cl₂ was stirred for 5 h at 0°-5° C., diluted with ether andfiltered over SiO₂. Removal of the volatiles in vacuo and purificationof the residue by HPLC using 14:1 hexanes:EtOAc as eluent provided 2.15g of the oily product. To the aldehyde in 20 mL anhydrous THF was addedpotaspium t-butoxide (24 mg). The solution was stirred for 60 min anddiluted with H₂ O and ether. The organic layer was washed with H₂ O andbrine and dried (MgSO₄). Removal of the volatiles in vacuo provided 2.08g of yellow solid which was taken forward without further purification

C.(E)-3-(7-(4-fluorophenyl)-9,9-dimethyl-1,4-dioxaspiro-{4,5}dec-7-en-8-yl)propenal(27)

In a manner similar to Scheme I, 26 (2.08 g, 7.17 mmol) was treated withthe LDA-derived anion of ethylidenecyclohexylamine (1.36 g, 10.8 mmol)in anhydrous THF at 0°-5° C. and after workup and purification by SiO₂using 6:1 hexanes:EtOAc as eluent provided 1.25 g of orange solid.

D. Methyl(E)-7-(7-(4-fluorophenyl)-9,9-dimethyl-1,4-dioxaspiro{4,5}dec-7-en-8-yl)-3,5-dihydroxyhept-6-enoate(28)

In a manner similar to Scheme I, 27 (1.25 g, 3.95 mmol) was treated withthe dianion of methyl acetoacetate (3.76 mmol) in anhydrous THF at 0°-5°C. Workup and purification by SiO₂ using 2:1 hexanes:EtOAc as eluentgave 0.95 g of orange oil. The ketone was reduced with triethylborane,NaBH₄, and methanol in anhydrous THF at -78° C. Workup and purificationby SiO₂ using 5:4 hexanes:EtOAc as eluent provided 0.80 g of the tansolid.

E.Trans-(E)-6-{2-{7-(4-fluorophenyl)-9,9-dimethyl-1,4-dioxaspiro{4,5}dec-7-en-8-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(29)

A solution of 28 (0.80 g, 1.84 mmol) and NaOH (2.8 mL of a 1N aqueoussolution) in 12 mL methanol was stirred for 2 h, cooled to 0°-5° C.,acidified to pH 2 with aqueous HCl and extracted with ether. Thecombined organic extracts were washed with H₂ O and brine and dried(MgSO₄). Removal of the volatiles in vacuo provided 0.60 g of yellowsolid. A solution of the carboxylic acid, DCC (0.295 q, 1.43 mmol) andDMAP (9 mg, 0.071 mmol) in 10mL anhydrous ether was stirred for 1,5 h at-10° C. and placed on a SiO₂ gel column. Elution with 5:4 hexanes:EtOAcand concentration in vacuo of the product rich fractions furnished 0.38g of white solid. mp 142°-4° C. Anal. C₃₂ H₂₇ FO₅. Theory C: 68.64; H:6.76. Found C: 69.12; H: 6.97.

EXAMPLE 4 (Scheme IV) A. Methyl2-(4-fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-2-en-1-carboxylate(31)

A solution of 4a (11.05 g, 38.1 mmol) and pyrrolidine (8.13 g, 0.114mol) in 11,5 mL of 5N HCl in methanol (57.1 mmol) and 100 mL chloroformwas stirred at ambient temperature overnight and the volatiles wereremoved in vacuo. The residue was dissolved in 100 mL methanol and 5NHCl methanol was added until the mixture became acidic (bromocresolgreen). To the solution was added NaCNBH₃ (2.40 g, 38.7 mmol) and thereaction was maintained at pH 3-5 by the dropwise addition of 5N HCl inmethanol. After stirring overnight the volatiles were removed in vacuo.The residue was diluted with ether and 1N NaOH. The organic layer waswashed with H₂ O and brine and dried (MgSO₄). Removal of the volatilesin vacuo and purification of the residue by HPLC using 1% Et₃ N in 1:1hexanes:EtOAc as the eluent provided 8.75 g of the oily product.

B.2-(4-Fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-1-en-1-carboxaldehyde(32)

In a manner similar to Scheme I, 31 was treated sequentially with LAH inTHF at 0°-5° C., sulfur trioxide pyridine complex in DMSO at ambienttemperature and Triton B in methanol at 0°-5° C. for 18 h. Workup andpurification afforded the oily product.

C.(E)-3-{2-(4-fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-1-en-1-propenal(33)

In a manner similar to Scheme I, 32 (3.80 g, 12.1 mmol) was treated withthe LDA-derived ahion of ethylidenecyclohexylamine (2.90 g, 23.2 mmol)in anhydrous ether. Workup and purification of the residue by HPLC using1% Et₃ N in 10:1 hexanes:EtOAc as eluent provided the dieneimine (2.4 g)The imine and oxalic acid (10 g) in 40 mL H₂ O was heated at 100° C. for2 h, cooled, diluted with saturated NaHCO₃ and ether. The organic layerwas washed with H₂ O and brine and dried (MgSO₄). Removal of volatilesin vacuo provided 2.27 g of gum which was taken forward without furtherpurification.

D. Methyl(E)-7-{2-(4-fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-1-en-1-yl}-3,5-dihydroxyhept-6-enoate(34)

In a manner similar to Scheme I, 33 (2.27 g, 6,65 mmol) was treated withthe LDA derived anion of methyl acetoacetate (7.98 mmol) followed bytriethylborane, methanol, and NaBH₄. Workup and purification by HPLCusing 1% Et₃ N in EtOAc as eluent provided the oily product.

E.

Trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-(pyrrolidin-1-yl)-6,6-dimethylcyclohex-1-en-1-yl}ethenyl)4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(35)

In a manner similar to Scheme I, 34 (0.19 g) was treated with 2N NaOH inmethanol at 0°-5° C. for 18 h, followed by ethyl chloroformate (0.254mmol) and Et₃ N in CH₂ Cl₂ at 0°-5° C. Workup and purification of theresidue by SiO₂ using 1% Et₃ N in EtOAc as eluent yielded the product.mp 120°-3° C. Anal. C₂₆ H₃₄ FNO₃ ·0.5 H₂ O: Theory C: 71,53; H: 8.08; N:3.21; Found C: 71.60; H: 8.17; N: 3.03.

EXAMPLE 5 (Scheme V) A.Trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-(ethoxy-carbonylmethoxy)-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-(t-butyldiuhenylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one(36)

To a mixture of 24 (0.17 gm, 0.27 mmol) and Rh₂ (OAc)₄ in 1,5 mL CH₂ Cl₂was added dropwise over 90 min. ethyl diazoacetate (200 μL, 1.93 mmol).The mixture was stirred for an additional 20 min. and the volatilesremoved in vacuo. Purification of the residue on SiO₂ by eluting with5:1 hexanes:EtOAc provided 0.12 gm of the oily product.

B.Trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-(ethoxycarbonylmethoxy)-6,6-dimethylcyclohexen-1-yl)-ethenyl)-4-hydroxy-3.4,5.6-tetrahydro-2H-pyran-2-one(37)

To a 0°-5° C. solution of 36 (0.11 gm) in 1 mL anhydrous THF was added0.1 mL of acetic acid and 0.75 mL of a 1.1 M THF solution oftetrabutylammonium flouride. The solution was slowly warmed to 25° C.,stirred overnight, diluted with ether, washed with saturated NaHCO₃ andbrine and dried (MgSO₄). Removal of the volatiles in vacuo andpurification of the residue on SiO₂ by eluting with 1:1 hexanes:EtOAcfurnished the solid product.

EXAMPLE 6 (Scheme VI) A.Trans-(E)-6-{2-{2-(4-flouro-3-methylphenyl)-4-phenylcarbamoyloxy-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-(t-butyldiphenylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one(38)

To a solution of 24 (0.258 g, 0.421 mmol) in 3 mL anhydrous DMF wasadded phenylisocyanate (52 μL, 0.463 mmol). The mixture was stirred for4 h, and phenylisocyanate (52 μL) was added again. The reaction wasstirred overnight, diluted with ether, washed with H₂ O and brine anddried (MgSO₄). Removal of the volatiles in vacuo and purification of theresidue with SiO₂ using 3:1 hexanes:EtOAc as eluents provided 0.210 gmof the white solid.

B.Trans-(E)-6-(2-(2-(4-flouro-3-methylphenyl)-4-phenylcarbamoyloxy-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(39)

In a manner similar to Scheme V, 38 (0.20 gm) was treated withtetrabutylammonium fluoride in THF and acetic acid and, after workup,purified by SiO₂ using 1:1 hexanes:EtOAc as eluent and yielded 0.101 gof product. mp 73°-5° C. Anal. C₂₉ H₃₂ FNO₅ : Theory C: 70.57; H: 6.54;N:2.84. Found C: 70.37; H: 6.94; N: 3.06.

EXAMPLE 7 (Scheme VII) A.Trans-(E)-6-{2-(2-(4-fluoro-3-methylphenyl)-4-ethylcarbonyldioxy-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-butyldiphenylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2one(40)

A solution of 24 (0.25 g, 0.408 mmol) and freshly distilled ethylchloroformate (81 μL, 0.816 mmol) in 3 mL anhydrous pyridine was heatedat 60° C. for 5 h, cooled, diluted with ether, washed with H₂ O, aqueousHCl and brine and dried (MgSO₄). Removal of the volatiles in vacuoprovided a residue which was purified by flash chromatography using 6:1hexanes--EtOAc as the eluent. Concentration in vacuo of the product richfractions provided 0.15 g of the off-white solid.

B.Trans-(E)-6-(2-(2-(4-fluoro-3-methylphenyl)-4-ethylcarbonyldioxy-6,6-dimethylcyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(41)

In a manner similar to Scheme V, 40 (0.15 g, 0.219 mmol) was treatedwith n-tetrabutylammonium fluoride (1.1 mmol) in THF. Workup andpurification by HPLC using 1:1 hexanes:EtOAc as eluent yielded 70 mg ofproduct. Anal. C₂₅ H₃₁ FO₆ : Theory C: 67.25; H: 7.00. Found C: 66.83;H:71.00.

EXAMPLE 8 (Scheme VIII) A.Trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-succinimido-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-(t-butyldiphenylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one(42)

To a solution of 24 (0.324 g, 0.52 mmol), succinimide (57.6 mg, 0.58mmol) and triphenylphosphine (0.153 gm, 0.58 mmol) in 3 mL anhydrous THFwas added dropwise diethyl azodicarboxylate (92 μL, 0.58 mmol). Themixture was stirred for 3 h and the volatiles removed in vacuo.Purification of the residue on SiO₂ by eluting with 1:1 hexanes:EtOAcprovided 0.13 gm of the oily product.

B.Trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-succinimido-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-hydroxy-4,5,6-tetrahydro-2H-pyran-2-one(43)

In a manner similar to scheme V, 42 (0.13 gm) was treated withtetrabutylammonium fluoride and the product was purified by SiO₂ with1,5:1 EtOAc:hexanes is the eluent. Concentration in vacuo of the productrich fractions provided 0.51 gm of the product. mp 71°-77° C. Anal. C₂₆H₃₀ FNO₅.0.25 H₂ O: Theory C: 67.89; H: 6.68; N: 3.04. Found C: 67.83;H: 6.95; N: 2.90.

EXAMPLE 9 (Scheme IX) A.Trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-phthalimido-6,6-dimethylcyclohexen-1-yl)ethenyl}-4-(t-butyldiphenylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one(44)

In a manner similar to Scheme VIII, 24 (0.242 gm), triphenylphosphine,(0.114 g), phthalimide (64 mg) and diethyl azodicarboxylate (68 μL)provided, after SiO₂ chromatography with 5:1 hexanes:EtOAc as eluent,0.16 gm of the oily product.

Trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-phthalimido-6,6-dimethylcyclohexen-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(45)

In a manner similar to Scheme VIII, 44 (0.15 gm) was treated withtetrabutylammonium fluoride and HOAc and provided, after purificationwith SiO₂ using 1:1 hexanes:EtOAc as eluent, 68 mg of the solid product.

In manner similar to the processes shown in the above Examples, thefollowing compounds are made:

Trans-(E)-6-[2-[8-(4-fluoro-3-methylphenyl)-3,3,10,10-tetramethyl-1,5-dithiaspiro[5.5]undec-8-en-9-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.1,5-dioxospiro[5.5]undec-8-en-9-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[8-(4-fluorophenyl)-2,3,9,9-tetramethyl-1,4-dithiaspiro[4.5]dec-7-en-8-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[-2-(4-fluoro-3-methylphenyl)-4-(3,4-difluorophenylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(4-pyridylcarbonylhydroxy)-6,6-dimethylcyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-E-(6-[2-[2-(4-fluoro-3-methylphenyl)-4-ethylcarbamoyloxy-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahyro-2H-pyran-2-one.

Trans-6-[2-[2-(4-chloro-3-methylphenyl)-4-(4-chloro-3-methylphenylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-6-[2-[2-(4-fluorophenyl)-4-(3-pyridyl-carbamoyloxy)-6,6-dimethyloyclohex-1-en-1-yl]-ethyl]4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-6-[2-[2-(4-flouorphenyl)-4-(5-indolylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-6-[2-[2-(4-fluorophenyl)-4-(3-quinolinylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]-ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-6-[2-[2-(4-flouro-3-methylphenyl)-4-(3-quinolinylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[2-(4-fluoro-3-hydroxymethyl)-4-(3-(diethylaminocarbonyl)propyloxy)-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(3-(ethoxycarbonyl)propyloxy)-6,6-dimethylcyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(3-(4-fluoro-3-methylbenzoyl)propyloxy)-6,6-dimethylcyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

Trans-(E)-6-[2-[2-(4-fluorophenyl)-4-(3-(2,6-dimethyl-4-pyridoyl)propyloxy)-6,6-dimethyl-cyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

The compounds of the present invention are useful as hypocholesterolemicor hypolipidemic agents by virtue of their ability to inhibit thebiosynthesis of cholesterol through inhibition of the enzyme HMG-CoAreductase. Having such ability, the compounds are incorporated intopharmaceutically acceptable carriers and administered to a patient inneed of such cholesterol biosynthesis inhibition orally or parenterally.Such pharmaceutical formulations to contain at least one compoundaccording to the invention.

Suitable carriers include diluents or fillers, sterile aqueous media andvarious non-toxic organic solvents. The compositions may be formulatedin the form of tablets, capsules, lozenges, trochees, hard candies,powders, aqueous suspensions, or solutions, injectable solutions,elixirs, syrups and the like and may contain one or more agents selectedfrom the group including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a pharmaceuticallyacceptable preparation.

The particular carrier and the ratio of active compound to carrier aredetermined by the solubility and chemical properties of the compounds,the particular mode of administration and standard pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate and dicalcium phosphate and various disintegrants suchas starch, alginic acid and certain complex silicates, together withlubricating agents such as magnesium stearate, sodium lauryl sulphateand talc, can be used in producing tablets. For a capsule form, lactoseand high molecular weight polyethylene glycols are among the preferredpharmaceutically acceptable carriers.

Where aqueous suspensions for oral use are formulated, the carrier canbe emulsifying or suspending agents. Diluents such as ethanol, propyleneglycol, and glycerin and their combinations can be employed as well asother materials.

For parenteral administration, solutions or suspensions of thesecompounds in aqueous alcoholic media or in sesame or peanut oil oraqueous solutions of the soluble pharmaceutically acceptable salves canbe employed.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Doses mayvary, depending on the age, severity, body weight and other conditionsof the patients but are ordinarily in the area of 5 mg/kg to 500 mg/kgof body weight in oral administration; such may, of course be given intwo to four divided doses. With other forms of administration equivalentor adjusted doses will be administered depending on the route ofadministration.

The utility of the claimed compounds is measured by the test methoddescribed hereunder. The method is based on the articles: "Purificationof 3-hydroxy-3-methylglutaryl-coenzyme A reductase from rat liver" byKleinsek et al., Proc. Natl. Acad. Sci. USA, Vol. No. 4, pp. 1431-1435,Apr. 1977 Biochemistry; "Mevinolin: A highly potent competitiveinhibitor of hydroxy methyl glutaryl-coenzyme A reductase and acholesterol-lowering agent" by Alberts et al., Proc. Natl. Acad. Sci.U.S.A., Vol 77, pp. 3951-3961, July 1980, Biochemistry; "Effects ofML-236B on cholesterol metabolism in mice rats: Lack ofhypocholesterolemic activity in normal animals" by Endo et et al.,Biochimica et Biophysica Acta, 575 (1979) 266-276; and "Evidence ofregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activityand cholesterol synthesis in nonhepatic tissues of rat" byBalasubramaniam et al., Proc. Natl. Acad. Sci. USA, Vol. 73, No. 8, pp.2564-2568, Aug. 1976, Biochemistry.

The method used (designated HMGR Screen) was as follows. Male rats wereacclimated to an alternate 12 hour light-dark cycle for a period of 2-3weeks. The animals, weighing 180-230 g, were fed ad libitum a rat chowcontaining 2% cholestyramine for 5 days prior to sacrifice at themid-dark period. Liver microsomes were prepared and HMGR enzyme wassolubilized from the microsomes by freeze-thaw manipulation in highionic strength buffer. The enzyme preparation was stored at -80° C. in300 μl portion samples. Prior to use, the enzyme was activated at 37° C.for 30 minutes in a reaction mixture. The reaction mixture contained ina volume of 240 μl: 0.14M potassium phosphate buffer (pH 7.0); 0.18MKCl; 3,5 mM EDTA; 10 mM dithiothreitol; 0.1 mg/ml BSA; 30,000 cpm of [¹⁴C]HMG-CoA; μM HMG-CoA, and 200 μg of solubilized enzyme with and withoutinhibitors (in 10 μl DMSO). After 5 minutes incubation at 37° C. thereaction was initiated with 0.2 mM NADPH. The final assay volume was 300μl. The reaction then was terminated with 100 μl of 1N HCl. After anadditional incubation for 15 minutes at 37° C. to allow for completelactonization of the product, the mixture was diluted with 3 ml GDW. Thediluted mixture was then poured over a 0.7×1.4 cm column containing100-200 mesh Bio-Rex ion-exchange resin (cloride form of Bio-Rad) whichwas equilibrated with distilled water. With this resin the unreacted [¹⁴C] HMG-CoA was adsorbed and the product [¹⁴ C] lactone was eluted (80%recovery) directly into scintillation vials. After the addition of 10 mlof Aquasol, radioactivities of the samples were measured in ascintillation counter. Result on compounds 13, 29, 35, 37, 139, 41, 43and 45 are shown in Table I (IC₅₀ μM).

                  TABLE I                                                         ______________________________________                                         ##STR9##                                                                     Com-                                                                          pound  X.sub.1                                                                              Z           Y          IC.sub.50 (μM)                        ______________________________________                                        13     Me     Chemical bond                                                                             S(CH.sub.2).sub.3 S                                                                      0.011                                    29     H      Chemical bond                                                                             O(CH.sub.2).sub.2 O                                                                      0.038                                    35     Me     H           C.sub.4 H.sub.8 N                                                                        >0.100                                   37     Me     H           EtOC(O)CH.sub.2 O                                                                        0.030                                    39     Me     H           PhNHC(O)    0.0018                                  41     Me     H           EtOC(O)O   0.042                                    43     Me     H           N-Succinimido                                                                             0.0080                                  45     Me     H           N-Phthalimido                                                                            0.100                                    ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR10## wherein A isCH₂ CH₂, CH═CH, or C═C;X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl,halogen, RO(CH₂)_(m) --, aryl, NR₁ R₂ or SO_(m) R₁ ; R, R₁, R₂ and Z areindependently: H or C₁₋₆ alkyl; Y is ##STR11## Q is NR₃ R₄ or OR₃ ; R₃and R₄ are independently: H, C₁₋₆ alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl selected from the group consistingof pyridyl, indolyl, quinolyl, substituted pyridyl, substituted indolyland substituted quinolyl; m is 0, 1 or 2; or a hydroxy acid orpharmaceutically acceptable salt thereof.
 2. A hypocholesterolemic,hypolipidemic pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 3. A hypocholesterolemic, hypolipidemicpharmaceutical composition of claim 2 wherein said compound is selectedfrom the group consistingof:trans-(E)-6-{2-{2-(4-fluoro-3-methylphenyl)-4-phenylcarbamoyloxy-6,6-dimethyclohex-1-en-1-yl)ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-{2-{2-(4-fluoro-3-hydroxymethyl)-4-(4-fluorophenylcarbamoyloxy)-6,6-dimethyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-6-{2-{2-(4-fluorophenyl)-4-(N-phenyl-N-methylcarbamoyloxy)-6,6-dimethylclohex-1-en-1-yl)ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-{2-{2-(4-chlorophenyl)-4-(3-(pyridylcarbamoyloxy)-6,6-dimethyclohex-1-en-1-yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-{2-{2-(4-fluorophenyl)-4-ethylcarbonyldioxy)-6,6-dimethyclohex-1-en-1-yl}ethyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.4. A hypocholesterolemic, hypolipidemic pharmaceutical composition ofclaim 2 wherein said compound is selected from the group consistingof:trans-(E)-6-{2-{2-(4-chloro-3-methylphenyl)-4-(4-chloro-3-methylphenylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1yl}ethenyl}-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[-2-(4-fluoro-3-methylphenyl)-4-(3,4-difluorophenylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(4-pyridylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;andtrans-E-(6-[2-[2-(4-fluoro-3-methylphenyl)-4-ethylcarbamoyloxy-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahyro-2H-pyran-2-one.5.Trans-6-[2-[2-(4-chloro-3-methylphenyl)-4-(4-chloro-3-methylphenylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.6.Trans-6-[2-[2-(4-fluorophenyl)-4-(3-pyridylcarbamoyloxy)-6,6-dimethyloyclohex-1-en-1-yl]-ethyl]4-hydroxy-3,4,5,6,-tetrahydro-2H-pyran-2-one.7.Trans-6-[2-[2-(4-flouorphenyl)-4-(5-indolylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]4hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.8.Trans-6-[2-[2-(4-fluorophenyl)-4-(3-quinolinylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]-ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.9.Trans-6-[2-[2-(4-flouro-3-methylphenyl)-4-(3-quinolinylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.10. A hypocholesterolemic, hypolipidemic pharmaceutical composition ofclaim 1 wherein said compound is selected from the group consistingof:trans-6-[2-[2-(4-chloro-3-methylphenyl)-4-(4-chloro-3-methylphenylcarbamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-6-[2-[2-(4-fluorophenyl)-4-(3-pyridyl-carbamoyloxy)6,6-dimethyloyclohex-1-en-1-yl]-ethyl]4-hydroxy-3,4,5,6,-tetrahydro-2H-pyran-2-one;trans-6-[2-[2-(4-flouorphenyl)-4-(5-indolylcabamoyloxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.11. A hypocholesterolemic, hypolipidemic pharmaceutical composition ofclaim 1 wherein said compound is selected from the group consistingof:trans-6-[2-[2-(4-fluorophenyl)-4-(3-quinolinylcarbamoyloxy)6,6-dimethylcyclohex-1-en-1-yl]-ethyl]-ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-6-[2-[2-(4-flouro-3-methylphenyl)-4-(3-quinolinylcarbonyldioxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.12. A method of inhibiting cholesterol synthesis in a patient in need ofsuch treatment comprising administering a pharmaceutical comopsitiondefined in claim
 2. 13. A compound of the formula ##STR12## wherein A isCH₂ CH₂, CH═CH, or C═C;X₁, X₂ and X₃ are independently: H, C₁₋₆ alkyl,halogen, RO(CH₂)_(m) --, aryl, NR₁ R₂ or SO_(m) R₁ ; R, R₁, R₂ and Z areindependently: H or C₁₋₆ alkyl; Y is --O(CR₁ R₂)_(n) C(O)Q; Q is NR₃ R₄or OR₃ ; R₃ and R₄ are independently: H, C₁₋₆ alkyl, aryl, substitutedaryl, heteroaryl or substituted heteroaryl selected from the groupconsisting of pyridyl, indolyl, quinolyl, substitutedpyridyl,substituted indolyl and substituted quinolyl; n is 1, 2 or 3; m is 0, 1or 2; or a hydroxy acid or pharmaceutically acceptable salt thereof. 14.Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-phenylcarbonyloxy-6,6-dimethyloxycyclohexen-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.15.Trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-ethylcarbonyldioxy-6,6-dimethyloxycyclohex-1-en-1-yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.16.Trans-(E)-6-[2-[2-(4-fluorophenyl)-4-(3-(2,6-dimethyl-4-pyridoyl)propyloxy)-6,6-dimethyl-cyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.17. A hypocholesterolemic, hypolipidemic pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 13and a pharmaceutically acceptable carrier.
 18. A hypocholesterolemic,hypolipidemic pharmaceutical composition of claim 17 wherein saidcompound is selected from the group consistingof:trans-6-[2-[2-(4-fluoro-3-methylphenyl)-4-ethoxycarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[2-(4-fluorophenyl)-4-(2-[ethoxycarbonyl)-ethoxy)-6,6-dimethylcyclohex-1-en-1-yl]ethenyl]-4-hydroxy3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[2-(4-fluoro-3-ethylphenyl)-4-(2-(4-fluoroanilinocarbonyl)ethoxy)-6,6-dimethylcyclohex-1-en-1-yl[ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[[2-(4-chlorophenyl)-4-(dimethylaminocarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl]ethynyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;andtrans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(4-methoxyanilinocarbonylmethoxy)-6,6-dimethylcyclohex-1-en-1-yl]ethyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.19. A hypocholesterolemic, hypolipidemic pharmaceutical composition ofclaim 17 wherein said compound is selected from the group consistingof:trans-(E)-6-[2-[2-(4-fluoro-3-hydroxymethyl)-4-(3-(diethylaminocarbonyl)propyloxy)-6,6-dimethylcyclohex-1-en-1-yl]-ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(3-(ethoxycarbonyl)propyloxy)-6,6-dimethylcyclohex-1-en-1-yl]-ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;andtrans-(E)-6-[2-[2-(4-fluoro-3-methylphenyl)-4-(3-(4-fluoro3-methylbenzoyl)propyloxy)-6,6-dimethylcyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;trans-(E)-6-[2-[2-(4-fluorophenyl)-4-(3-(2,6-dimethyl-4-pyridoyl)propyloxy)-6,6-dimethyl-cyclohex-1-en-1yl]ethenyl]-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.20. A method of inhibiting cholesterol synthesis in a patient in need ofsuch treatment comprising administering a pharmaceutical compositiondefined in claim 17.